Historical Reference Page
This is a historical reference page. This trial preceded the modern evidence base. It is presented as a predecessor reference. See POINT (2018) for the modern successor trial that defined the appropriate short-duration window for DAPT in the cerebrovascular subset of patients CHARISMA studied.
CHARISMA Trial: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance
In patients with established cardiovascular disease or multiple cardiovascular risk factors, does adding clopidogrel to aspirin reduce MI, stroke, or cardiovascular death over a median 28-month follow-up?
Bhatt et al. (NEJM 2006) · doi:10.1056/NEJMoa060989 · 15,603 patients
Population
Included
- Age 45 years or older
- Established cardiovascular disease (prior MI, ischemic stroke, or symptomatic PAD) OR multiple cardiovascular risk factors without established disease
- Stable on aspirin (75–162 mg/day)
- No recent unstable coronary syndrome requiring immediate revascularization
Excluded
- Need for oral anticoagulation or NSAID therapy
- High bleeding risk (recent surgery, active peptic ulcer)
- Prior intolerance to aspirin or clopidogrel
- Severe renal impairment (creatinine above 2.0 mg/dL)
- Life expectancy less than 2 years
Primary Outcome — MI/Stroke/Cardiovascular Death at Median 28 Months
15,603 patients; aspirin + clopidogrel vs aspirin alone; established CV disease or high-risk
In 15,603 patients with established cardiovascular disease or multiple cardiovascular risk factors, aspirin plus clopidogrel did not significantly reduce the composite of myocardial infarction, stroke, or cardiovascular death over a median 28 months. The primary endpoint occurred in 6.8% of the combination group versus 7.3% of the aspirin-alone group (relative risk 0.93, 95% CI 0.83 to 1.05, P=0.22). A pre-specified symptomatic subgroup analysis showed a nominally favorable signal in patients with prior symptomatic atherothrombotic disease (RR 0.88, 95% CI 0.77 to 0.99), interpreted as hypothesis-generating, while the asymptomatic primary-prevention subgroup showed excess harm (RR 1.20, 95% CI 0.91 to 1.59). Overall there was no significant benefit and a clear bleeding excess with combination therapy.
Visualization not shown for predecessor reference pages. See source paper for figures.
Trial Design
CHARISMA enrolled patients from two populations: established symptomatic atherothrombotic disease (prior MI, ischemic stroke, or symptomatic peripheral arterial disease) and asymptomatic patients with multiple cardiovascular risk factors. All received aspirin at country-standard dose (75–162 mg/day) and were randomized to clopidogrel 75 mg/day or matching placebo. The trial was conducted across 768 centers in 45 countries with a median 28-month follow-up, far longer than the short-duration DAPT studied in CHANCE (2013) and POINT (2018). The duration difference is central to understanding why CHARISMA was negative while short-term trials were positive.
Safety
Moderate bleeding occurred in 2.1% of the combination group versus 1.3% of the aspirin-alone group (P<0.001). Severe bleeding was similar between groups. There was no significant difference in fatal bleeding. The bleeding excess persisted across the 28-month treatment period, with absolute risk increasing over time.